title: Oxazolopyridines and thiazolopyridines as monoamine oxidase B inhibitors for the treatment of Parkinson's disease.
abstract: In Parkinson's disease, the motor impairments are mainly caused by the death of dopaminergic neurons. Among the enzymes which are involved in the biosynthesis and catabolism of dopamine, monoamine oxidase B (MAO-B) has been a therapeutic target of Parkinson's disease. However, due to the undesirable adverse effects, development of alternative MAO-B inhibitors with greater optimal therapeutic potential towards Parkinson's disease is urgently required. In this study, we designed and synthesized the oxazolopyridine and thiazolopyridine derivatives, and biologically evaluated their inhibitory activities against MAO-B. Structure-activity relationship study revealed that the piperidino group was the best choice for the R(1) amino substituent to the oxazolopyridine core structure and the activities of the oxazolopyridines with various phenyl rings were between 267.1 and 889.5nM in IC50 values. Interestingly, by replacement of the core structure from oxazolopyrine to thiazolopyridine, the activities were significantly improved and the compound 1n with the thiazolopyridine core structure showed the most potent activity with the IC50 value of 26.5nM. Molecular docking study showed that van der Waals interaction in the human MAO-B active site could explain the enhanced inhibitory activities of thiazolopyridine derivatives.
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology, Hwarangro 14-gil-5, Seongbuk-gu, Seoul 136-791, Republic of Korea.
authors.forename: Hye Ri
authors.initials: HR
authors.lastname: Park
authors.forename: Jiyoon
authors.initials: J
authors.lastname: Kim
authors.forename: Taekeun
authors.initials: T
authors.lastname: Kim
authors.forename: Seonmi
authors.initials: S
authors.lastname: Jo
authors.forename: Miyoung
authors.initials: M
authors.lastname: Yeom
authors.forename: Bongjin
authors.initials: B
authors.lastname: Moon
authors.forename: Il Han
authors.initials: IH
authors.lastname: Choo
authors.forename: Jaeick
authors.initials: J
authors.lastname: Lee
authors.forename: Eun Jeong
authors.initials: EJ
authors.lastname: Lim
authors.forename: Ki Duk
authors.initials: KD
authors.lastname: Park
authors.forename: Sun-Joon
authors.initials: SJ
authors.lastname: Min
authors.forename: Ghilsoo
authors.initials: G
authors.lastname: Nam
authors.forename: Gyochang
authors.initials: G
authors.lastname: Keum
authors.forename: C Justin
authors.initials: CJ
authors.lastname: Lee
authors.forename: Hyunah
authors.initials: H
authors.lastname: Choo
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D008995:Monoamine Oxidase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D010080:Oxazoles / Q000737:chemistry*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry*
chemical_list: D008996:Monoamine Oxidase Inhibitors; D010080:Oxazoles; D011725:Pyridines; D011994:Recombinant Proteins; D013844:Thiazoles; D008995:Monoamine Oxidase; D004298:Dopamine
keywords: MAO-B; Monoamine oxidase B; Oxazolopyridine; Parkinson’s disease; Thiazolopyridine